ABSTRACT Glioblastoma (GBM) is the most common and the most lethal brain cancer. Unfortunately, there has been tragically little therapeutic progress over the last 30 years. Surgery provides modest benefit, the blood-brain barrier (BBB) limits drug access, and GBM cells are resistant to radiation and to the leading chemotherapy, temozolomide. Targeted therapies for GBM have yielded disappointing results in trials to date. The challenges inherent in developing effective GBM therapeutic approaches have become increasingly clear, and include resistance to standard treatments, drug delivery into the tumor, a subpopulation of stem-like GBM cells (GSCs), and genetic complexity and molecular adaptability of GBM. GBM tumors display a cellular hierarchy of differentiation states, in which GSCs maintain a dynamic balance between the state of self-renewal and differentiation. A myriad of molecular signaling pathways crucial for the normal brain development also play important roles in glioma initiation and progression. We previously demonstrated that MET receptor tyrosine kinase signaling is a crucial regulator of GSCs. Recent studies have implicated that various neurotransmitter signaling can promote tumor growth and progression via maintaining stem cell state. Our recent studies and preliminary data have discovered that dopamine receptor subtype 2 (DRD2), a key receptor of dopamine signaling, promoted GBM growth via regulating the stem cell state of GSCs. Unexpectedly, DRD2 was highly expressed in clinical GBM specimens, with preferential expression in GSCs, compared to normal brain tissue. Mechanistically, DRD2 facilitated proliferation and clonogenic growth of GBM cells via activation of MET. This finding is highly relevant because MET signaling is frequently hyperactive in GBMs as a key regulator of cancer stem phenotype and GBM radio-resistance, and it is a well-recognized therapeutic target in GBM. Importantly, DRD2 knockdown or an FDA-approved DRD2 antagonist-mediated DRD2 inhibition potently inactivated oncogenic signaling pathways, diminished clonogenic growth of GSCs, and impeded GBM growth in orthotopic xenograft models. Furthermore, we found a strong synergistic anti- tumor effect by combination of MET inhibitor and DRD2 antagonist in a subset of GBM. This project will interrogate the roles of MET-DRD2 signaling in GSC self-renewal and GBM progression, and elucidate the mechanisms of oncogenic DRD2 signaling at the molecular level (Aim 1), and test therapeutic efficacy of FDA- approved antipsychotic drugs and novel inhibitory peptides that can specifically block the interaction between DRD2 and MET (Aim 2), and determine therapeutic efficacies of these targeting reagents alone or in combination with standard therapies in preclinical patient GBM-derived orthotopic tumor models and identify the biomarkers that predict therapeutic response (Aim 3). We anticipate that completion of these proposed studies will yield a new paradigm for cancer stem cell biology and provide a novel and effective therapeutic approach, which may lead to the translation into improved therapies.